Trefoil factor 2 expressed by the murine pancreatic acinar cells is required for the development of islets and for beta cell function during aging

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ABSTRACT Exocrine-to-endocrine crosstalk in the pancreas is crucial to maintain beta cell function. However, the molecular mechanisms underlying this crosstalk are largely undefined. Trefoil factor 2 (Tff2) is a secreted factor known to promote the proliferation of beta cells in vitro, but its physiological role in vivo in the pancreas is unknown. Also, it remains unclear which pancreatic cell type expresses Tff2 protein. We therefore created a mouse model with a conditional knockout of Tff2 in the murine pancreas. We find that the Tff2 protein is preferentially expressed in acinar but not ductal or endocrine cells. Tff2 deficiency in the pancreas reduces beta cell mass on embryonic day 16.5. However, homozygous mutant mice are born without a reduction of beta cells and with acinar Tff3 compensation by day 7. When mice are aged to 1 year, both male and female homozygous and male heterozygous mutants develop impaired glucose tolerance without affected insulin sensitivity. Perifusion analysis reveals that the second phase of glucose-stimulated insulin secretion from islets is reduced in aged homozygous mutant compared to controls. Collectively, these results demonstrate a previously unknown role of Tff2 as an exocrine acinar cell-derived protein required for maintaining functional endocrine beta cells in mice. Article Highlights: · Exocrine-to-endocrine crosstalk is important in maintaining pancreatic cell homeostasis, but the molecular mechanisms remain largely undefined. · In the pancreas, the physiological role of the secreted factor Tff2 and the cell type that expresses Tff2 has been unclear. · Pancreatic acinar cells are the major cell type expressing Tff2 protein, and specific loss of Tff2 in the pancreas reduces beta cells during development and attenuates glucose-stimulated insulin secretion during aging in conditional Tff2 knockout mice. · Tff2 is a positive exocrine-produced factor required for the development and function of endocrine beta cells, which has implication in diabetes disease progression and therapy.

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